Diabetes is a disease with chronic hyperglycemia as a cardinal sign and develops by absolute or relative deficiency of insulin activity. Clinically, diabetes is roughly classified by the characteristics into insulin-dependent diabetes (referred to as “type 1 diabetes” hereinafter) and non-insulin-dependent diabetes (referred to as “type 2 diabetes” hereinafter). In type 2 diabetes, which accounts for approximately 90% of diabetic patients, decrease of insulin secretion from the pancreatic β-cells is one of major causes of the onset, and postprandial hyperglycemia caused by early disorder in insulin secretion is particularly recognized. Presently, sulfonylurea drug (SU drug) is the mainstream as the insulin secretagogue, but it is likely to cause hypoglycemia and known to cause secondary ineffectiveness due to pancreatic exhaustion following long-term administration. Moreover, SU drug is effective to control blood glucose between meals, but has difficulty in suppressing postprandial hyperglycemia. Recent large-scale clinical trials have confirmed that remedying postprandial hyperglycemia is critical in controlling diabetic complications and diabetic development (Non-Patent Document 1). It is also reported that arteriosclerosis develops only during periods of the postprandial hyperglycemia and that the persistence of minor postprandial hyperglycemia increases mortality caused by cardiovascular disease or the like (Non-Patent Documents 2 and 3). This indicates that postprandial hyperglycemia is, even at minor levels, an independent risk factor of cardiovascular death. From the above background, attention has been paid to importance and necessity for medications against postprandial hyperglycemia. Hence, drugs having promoting activity on insulin secretion are considered to have an appropriate profile to remedy postprandial hyperglycemia and/or fasting blood glucose and to be useful for treating and preventing type 1 and type 2 diabetes.
WO 00/31047 pamphlet (Patent Document 1) discloses cyclopentane-condensed pyrimidine derivatives as compounds with activity to increase cyclic guanosine monophosphate (cGMP) level by activation of soluble guanylate cyclase, and diabetes is included in examples of diseases or morbidity in which increase in cGMP level is desired or said compounds can be used for therapy and prevention thereof. However, the document gives neither specific disclosure of the compounds of the present invention nor specific data indicating their applicability to diabetes therapy such as promoting activity on insulin secretion.
WO 00/46214 pamphlet (Patent Document 2) discloses cyclohexane-condensed pyrimidine derivatives as compounds with activity to increase cyclic guanosine monophosphate (cGMP) level by activation of soluble guanylate cyclase, and diabetes is included in examples of diseases or morbidity in which increase in cGMP level is desired or said compounds can be used for therapy and prevention thereof. However, the document gives neither specific disclosure of the compounds of the present invention nor specific data indicating their applicability to diabetes therapy such as promoting activity on insulin secretion.
WO 03/049739 pamphlet (Patent Document 3) discloses condensed pyrimidine derivatives as glycogen synthase kinase-3 (GSK-3) inhibitors and describes diabetes as an example of diseases for which these compounds are useful, that is, diseases caused by action of GSK-3. However, none of compounds of the present invention are specifically disclosed therein, and there are not disclosed specific data indicating applicability of said compounds to diabetes therapy such as promoting activity on insulin secretion, either.
WO 2004/065391 pamphlet (Patent Document 4) discloses thiophene-condensed pyrimidine derivatives substituted with a cyano group as phosphodiesterase 7 (PDE 7) inhibitors and describes type 1 and type 2 diabetes as examples of diseases that are expected to be improved by inhibition of PDE 7. However, neither compounds of the present invention are specifically disclosed, nor are specific data indicating their applicability to diabetes therapy such as promoting activity on insulin secretion.
Japanese Patent Laid-Open Publication H4-224580 (Patent Document 5) discloses nitrogen-containing ring-condensed pyrimidine derivatives as compounds with bactericidal activity, but does not specifically disclose the compounds of the present invention. Neither description nor suggestion is given on applicability of said compounds to diabetes therapy including promotion of insulin secretion, either.
WO 2004/087056 pamphlet (Patent Document 6) discloses condensed pyrimidine derivatives as transforming growth factor-beta (TGF-β) inhibitors, but does not specifically disclose the compounds of the present invention. The document gives neither description nor suggestion on applicability of said compounds to diabetes therapy including promotion of insulin secretion, either.
EP 0 276 057 (Patent Document 7) discloses pyrimidine derivatives condensed with a sulfur-containing ring as β-adrenaline blockers, but the document neither specifically discloses the compounds of the present invention nor gives description or suggestion on applicability of said compounds to diabetes therapy including promotion of insulin secretion.
WO 2005/014558 (Patent Document 8) discloses condensed pyrimidine derivatives as ion channel inhibitors, but does not specifically disclose the compounds of the present invention. It neither describes nor suggests that applicability of said compounds to diabetes therapy including promotion of insulin secretion.
Pyrimidine derivatives condensed with a sulfur-containing ring are also known as intermediates in synthesis of C60 derivatives (Non-Patent Documents 4 and 5).
Non-Patent Document 1: N. Engl. J. Med., 329, 977-986, 1993
Non-Patent Document 2: Lancet, 354, 617, 1999
Non-Patent Document 3: Brit. Med. J., 321, 405-413, 2000
Non-Patent Document 4: Tetrahedron, 54(37), 11141-11150, 1998
Non-Patent Document 5: Tetrahedron Letters, 38(14), 2557-2560, 1997
Patent Document 1: WO 00/31047
Patent Document 2: WO 00/46214
Patent Document 3: WO 03/049739
Patent Document 4: WO 2004/065391
Patent Document 5: Japanese Patent Laid-Open Publication H4-224580
Patent Document 6: WO 2004/087056
Patent Document 7: EP 0 276 057
Patent Document 8: WO 2005/014558